We conducted a comprehensive analysis of transcription of a candidate histone methyltransferase, Setdb2, in human and mouse tissues, revealing tissue-specific expression of alternatively spliced and chimeric transcripts. We found in-frame fusion transcripts linking Setdb2 to an adjacent independent gene, Phf11, which encodes a zinc finger-containing plant homeodomain motif. We previously found several protein-binding partners for the putative histone methyltransferases using yeast two hybrid screens; these binding partners now have been validated by co-immunoprecipitation experiments. Further functional characterization of interactions between Setdb2 and the identified binding partners, which include an unannotated protein and other biologically interesting proteins, has been conducted. We have generated a conditional knockout mouse model lacking Setdb2 located on a frequently deleted chromosomal region. Phenotypic characterization of these knockouts on various mouse strain backgrounds has begun. The knockout mice could comprise a new model for chronic lymphocytic leukemia, for asthma, and/or for other cancers or human diseases. Specific antibodies against mouse and human Setdb2 have been developed. We have expressed recombinant Setdb2 in baculovirus to facilitate characterization of its biochemical activities.